We recently observed three occurrences of false-positive results for
phencyclidine (PCP) on urine samples tested with the Syva® RapidTest
d.a.u.® 9 Test Panel (Syva Company, subsidiary of Dade Behring
Inc.). The RapidTest d.a.u. 9 device is a single-use, one-step,
solid-phase immunochromatographic assay for the qualitative,
discrete detection of several drugs/drug metabolites in human urine
(1). The urine samples were collected from three different patients
who were seen in our Emergency Department within 3–4 weeks after we
had implemented the RapidTest device in our laboratory (Danbury
Hospital). Because PCP is not a commonly used drug in our locale and
the rare positive results have usually been confirmed as false
positives, three positive PCP results in such a short time period
immediately aroused suspicion.

Patient A was a 52-year-old male with schizoaffective disorder who
was admitted to the psychiatry service. Patient B was a 93-year-old
female from a nursing home who was admitted with a hip fracture.
Patient C was a 50-year-old female admitted for opiate and
benzodiazepine overdose. None of these patients had a history of PCP
use or presented with symptoms consistent with use of this drug.

Patient A's urine gave negative results for all other drugs tested
with the RapidTest. Patient B's urine also tested positive for
benzodiazepines and barbiturates; these results could be attributed
to medications documented in this patient's medical record:
lorazepam, clonazepam, and phenytoin (the latter is listed in the
RapidTest package insert as an interferent in the barbiturates
assay). Patient C's urine also tested positive for benzodiazepines
and opiates; again, these results were consistent with this
patient's known medications (lorazepam and hydrocodone). None of the
patients was receiving dextromethorphan, diphenhydramine, ibuprofen,
imipramine, meperidine, mesoridazine, or thioridazine—drugs known to
produce false-positive results with other PCP immunoassays. The only
drug that appeared on the medication lists of all three patients was
venlafaxine, a relatively new antidepressant marketed as Effexor®
(Wyeth-Ayerst Pharmaceuticals, Inc.) (2). We therefore suspected
that this drug and/or one or more of its metabolites were the cause
of these false-positive results via cross-reactivity with the anti-
PCP antibodies used in the RapidTest devices (cutoff concentration
for PCP, 25 µg/L).

Negative results were obtained when the same urine samples from
these three patients were tested with the Syva Emit II Plus PCP
assay (25 µg/L cutoff) on the Roche Cobas MIRA analyzer (performed
at Danbury Hospital). Similarly, analysis by two other single-use
immunochromatographic devices, OnTrak TesTstik PCP (Roche
Diagnostics) and Biosite Triage 8 DOA (Biosite Diagnostics) also
gave negative results for PCP (both 25 µg/L cutoff; performed at
Hartford Hospital), and gas chromatographic-mass spectrometric
analysis did not detect PCP (5 µg/L limit of detection; performed at
Hartford Hospital). Of note, we also encountered a "true-positive"
PCP sample from an 18-year-old male patient admitted with head
trauma; this urine tested positive for PCP by the RapidTest, Emit,
and gas chromatographic-mass spectrometric methods and thus served
as a "positive control".

Venlafaxine undergoes both O- and N-demethylation, with the major
metabolite, O-desmethylvenlafaxine (ODV), also exhibiting
antidepressant activity. An average of 87% of a labeled oral dose is
excreted in a 48-h urine, with 5% excreted as parent drug, 29–48% as
ODV, 6–19% as di-N-desmethylvenlafaxine, and 0.2–7.4% as mono-N-
desmethylvenlafaxine (2). To further test our hypothesis that
venlafaxine and/or its metabolites were responsible for these false-
positive results, we obtained pure samples of venlafaxine and the
ODV metabolite from Wyeth-Ayerst Research, the manufacturer of this
drug. We prepared solutions of venlafaxine and ODV in drug-free
urine at final concentrations of 106, 105, 104, 103, and 102 µg/L
venlafaxine or ODV and tested these solutions with both the Emit II
and RapidTest PCP assays. The RapidTest gave a clearly positive PCP
result (no signal line indicates positive result) at a concentration
of 106 µg/L of either venlafaxine or ODV and equivocal or borderline
results (extremely faint, barely visible line) at 105 µg/L of either
venlafaxine or ODV, whereas the Emit II assay gave negative results
at all concentrations. Additional testing narrowed the concentration
where the RapidTest became clearly positive for PCP to somewhere
between 1 x 105 and 2 x 105 µg/L of either venlafaxine or ODV,
indicating similar cross-reactivities for these two compounds. From
these data, we calculated a cross-reactivity of between 0.0125% and
0.025% for both the parent drug and metabolite, using the 50%
displacement method described by Miller and Valdes (3). Although at
face value this appears to be a very low degree of cross-reactivity,
it becomes clinically significant if combined concentrations of
venlafaxine and ODV of 1 x 105 µg/L are present in a urine sample.

According to the literature, predicted steady-state plasma
concentrations of venlafaxine and ODV in healthy individuals
receiving daily 150-mg doses are estimated as 70 and 254 µg/L,
respectively (2). These concentrations are approximately three
orders of magnitude lower than those that were found to give
positive results in our addition experiments. Although we could find
no published data on urine concentrations of venlafaxine and ODV, we
learned that combined concentrations of these two substances on the
order of 1 x 105 µg/L have indeed been measured in the urine of
patients taking therapeutic doses of venlafaxine (K-T. J. Yeo,
personal communication). Combined with the results of our addition
experiments, this provides strong evidence that the false-positive
results we observed were caused by cross-reactivity of venlafaxine
and ODV with the RapidTest PCP assay.

Venlafaxine, designated (R/S)-1-[2-(dimethylamino)-1-(4-
methoxyphenyl)ethyl] cyclohexanol, is a phenethylamine derivative
that is chemically unrelated to tricyclic, tetracyclic, and other
antidepressants. It is the first antidepressant in a new drug class
referred to as the serotonin noradrenergic reuptake inhibitors
(SNaRIs) (4). Aside from possessing phenyl and cyclohexyl groups,
venlafaxine bears little structural similarity to phencyclidine [1-
(1-phenylcyclohexyl)piperidine; see Fig. 1 ]. Given this structural
dissimilarity, it is somewhat surprising that venlafaxine or any of
its desmethyl metabolites would cross-react with the anti-PCP
antibody used in the RapidTest device. However, other examples of
unexpected interferences with immunoassays for drugs of abuse have
been well documented in the literature, e.g., oxaprozin with the
Emit assay for benzodiazepines (5) and efavirenz with the CEDIA test
for cannabinoids (6)(7).

In conclusion, we believe our data strongly implicate venlafaxine
and ODV as the agents responsible for the false-positive PCP results
we observed with the RapidTest device. We have reported our findings
to the manufacturer and recommend that all laboratories using these
devices be made aware of this cause of false-positive results. Until
this interference is eliminated, we have implemented a procedure
where all positive PCP results obtained with the Rapid Test must be
verified with the Emit II Plus PCP assay before being reported to
our Emergency Department.

Acknowledgments

We gratefully acknowledge the generous contribution of pure samples
of venlafaxine and ODV from Wyeth-Ayerst Research, Princeton, NJ.